Neuroendocrine Disturbances Following Traumatic Brain Injury

By Stefanie N. Howell, Ph.D., CBIS, Centre for Neuro Skills, and Brent E. Masel, M.D., Centre for Neuro Skills and University of Texas Medical Branch

Traumatic brain injury (TBI) is a major cause of disability, with an estimated 5.3 million people living with disabilities secondary to a TBI in the U.S. alone. Often, survivors may seem to make a full physical recovery while being left with more subtle, “invisible” disabilities, which are likely to impact daily functioning. Examples include disturbed affect, hypervigilance, cognitive deficits, fatigue, and autonomic dysregulation. These chronic symptoms may be tied to brain injury induced dysregulation of the neuroendocrine system and may ultimately contribute to posttraumatic morbidity.

The impact of brain injuries to the neuroendocrine system

Biomechanical forces at the time of a TBI frequently impact the diencephalon, an area located deep within the center of the brain, just above the brainstem. Two main structures in the diencephalon, the hypothalamus and pituitary gland (the hypothalamic-pituitary system (HPS)), comprise a feedback loop which sends signals from the hypothalamus (releasing hormones) to the pituitary gland, which then releases/distributes hormones to a variety of other bodily systems, including the adrenal and thyroid glands, reproductive organs, skin, bone, and muscle. Dysregulation of this system may have widespread effects on mood, memory, metabolism, muscle mass, energy, stress, libido, and reproduction.

This “post-traumatic hypopituitarism” (PTHP) has been increasingly recognized as a common sequelae of TBI, which requires close monitoring due to the potential for symptoms to be overlooked as possible side effects of medications, and the possible transient, permanent, or fluctuating nature of the brain injury itself.

While PTHP does occur in mild injuries, it is more common in moderate to severe injuries and may evolve or resolve over time. In the acute phase after TBI, hormonal changes may be attributed to the body and the brain’s response to the injury, while alterations that persist into the subacute to chronic phase are more likely to reflect hypothalamic pituitary dysfunction. The exact timing of the development of PTHP cannot be predicted and may surface more than one year post-injury.

The hypothalamic-pituitary system: Why is it vulnerable?

The HPS is particularly vulnerable to TBI due to its vascular and anatomical characteristics. The pituitary, a pea-sized gland attached to the brain by a fragile stalk, is located in a bony enclosure, the sella turcica. Trauma may damage the HPS directly or cause secondary damage by inducing hemorrhage, increasing intracranial pressure, and/or producing changes in cerebral blood flow (ischemia), metabolism, cytotoxicity, or inflammation. The pituitary, with its anterior and posterior lobes, is also at high risk due to its blood supply. The anterior pituitary, which releases the majority of pituitary hormones, receives no direct arterial blood-supply. Instead, it receives the bulk of its supply from long hypophyseal vessels, which are more susceptible to damage.

Hypothalamic-Pituitary System Axis Dysfunction

There are several different ways that dysfunction can occur in the hypothalamic-pituitary system:

Hypothalamic-Pituitary Somatotropic Axis:

Disruption of the HPS axis may result in Growth Hormone (GH) deficiency. Synthesized in the anterior pituitary gland, GH stimulates the production and release of insulin-like growth factor-1 (IGF-1) and has been identified as crucial in nervous system development, neuroprotection, and neuro-regeneration, as well as in the regulation of appetite, cognitive function, energy, memory, mood, sleep, and general well-being. GH receptors have been found on the surface of most cells, indicating that levels of GH will impact nearly all tissues and organs either directly, or via growth factors. The prevalence of GH deficiency (GHD) post-TBI is highly variable, which may be attributed to the timing and method of diagnosis. However, 30-45% of patients with chronic TBI have been diagnosed with GHD. Individuals with TBI presenting with GHD often have issues with decreased muscle mass and bone density, fatigue, impairments in memory, attention, and cognitive flexibility, and ultimately a substantial decrease in quality of life.

Hypothalamic-Pituitary Gonadal Axis:

Dysregulation of this axis involves alterations in hypothalamic release of gonadotropin releasing hormone (GnRH) and/or damage to the pituitary cells responsible for the gonadal hormones, and therefore, may impact sex hormones such as estradiol, progesterone, and testosterone. In men, hypogonadism is typically associated with low levels of testosterone and in women, with decreases in estradiol. Hypogonadism presents acutely following TBI and has been found to persist in up to 37% of male patients. In females, delayed resumption of menses or even cessation of menses is well known following a TBI.

Hypothalamic-Pituitary Adrenal Axis:

One of the roles of this axis, which functions through a negative feedback loop, is to regulate our stress response. When we experience something stressful in our environment, the hypothalamus releases corticotropin-releasing hormone (CRH), which triggers the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. This signal then travels to the adrenal glands where cortisol is released. Cortisol initiates several changes in our body that help us deal with stress, i.e., our “fight or flight response” for example, increasing blood pressure and heart rate. In a functioning feedback loop, high cortisol levels in the blood trigger the hypothalamus to decrease the release of CRH, thereby stopping the stress response. Hyperresponsiveness to stress and dysregulation of this axis has been reported following experimental TBI, the duration of which appears to be dependent upon TBI severity. This hyperresponsiveness has been implicated in depression, anxiety, mood swings, irritability, and impaired learning/memory.

Hypothalamic-Pituitary Thyroid Axis:

Although observed less frequently following TBI, given the widespread metabolic effects of thyroid hormones, persistent disruption of this axis can have substantial consequences. Also functioning through a negative feedback loop, dysregulation of thyroid hormones has been shown to impair cognition, mood, and energy levels. In addition to this axis being disrupted by the injury itself, thyroid hormone activity is influenced by other endocrine signals and compounds, such as cortisol and gonadal hormones.

Pediatrics

Certainly, children can develop PTHP, with reported incidences of 8-29% at one-year post-injury. Children may have altered fat distribution, impaired growth, altered school performance, and delayed puberty. Children with suspected PTHP should be referred to a pediatric endocrinologist.

Diagnosis of PTHP

The following tests can be obtained by any medical provider:

• Growth hormone: Insulin-like Growth Factor 1
• Gonadotropins: Males—LH, FSH, Prolactin and morning free Testosterone. Females—FSH, LH, Prolactin and estradiol. (No testing needed if having normal menses)
• Adrenals: morning cortisol
• Thyroid: TSH and free T4

Although there are varying opinions on the timing (due to potential spontaneous recovery), if PTHP is suspected, patients should be screened no sooner than 6-12 months post injury. Patients with abnormal testing (and/or a high index of suspicion for PTHP) should be referred to an endocrinologist.

Treatment of PTHP

Any medical provider may initiate hormone replacement; however, it is best that someone with PTHP be treated by an endocrinologist knowledgeable in this field. Depending on the abnormality, treatment may be as simple as taking a daily pill. Diagnosis and treatment of GHD is more complex, and replacement requires a daily injection. Most patients with PTHP see an improvement in their symptoms with appropriate replacement.

Conclusion

Due to the high prevalence, the association with poor outcomes, and the relative ease of treatment, dysregulation of the neuroendocrine system is frequently becoming an area of early identification and treatment in order to prevent long-term neurological consequences. Symptomatic individuals with chronic TBI should strongly be considered for pituitary diagnostic testing and treatment.

References

1. Centers for Disease Control and Prevention. Report to Congress: Traumatic Brain Injury in the United States. Accessed 2022, https://www.cdc.gov/traumaticbraininjury/data/index.html.
2. Bartke, A. (2011). Pleiotropic Effects of Growth Hormone Signaling in Aging. Trends in Endocrinology and Metabolism, 22(11), 437-442.
3. Kreber, L.A., Griesbach, G.S., Ashley, M.J. (2016). Detection of Growth Hormone Deficiency in Adults with Chronic Traumatic Brain Injury. J Neurotrauma, 33(17), 1607-1613.
4. Wagner, A. K., Brett, C. A., McCullough, E. H., Niyonkuru, C., Loucks, T. L., Dixon, C. E., … Berga, S. L. (2012). Persistent hypogonadism influences estradiol synthesis, cognition and outcome in males after severe TBI. Brain Inj, 26(10), 1226-1242.
5. Colantonio, A., Mar, W., Escobar, M., Yoshida, K., Velikonja, D., …Cullen, N. (2010). Women’s Health Outcomes After Traumatic Brain Injury. Journal of Women’s Health, 19(6).
6. Griesbach, G. S., Hovda, D. A., Tio, D. L., & Taylor, A. N. (2011). Heightening of the stress response during the first weeks after a mild traumatic brain injury. Neuroscience, 178, 147-158.
7. Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002). Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev, 23(1), 38-89.

---

This article originally appeared in Volume 16, Issue 4 of THE Challenge! published in 2022.